Abstract

We routinely encounter pathogens as part of life in a microbial world. Fortunately, most such encounters do not result in clinical disease. However, some of us demonstrate heightened susceptibility to infection by specific pathogens, which we recognize increasingly as monogenic disorders affecting innate immune defense. Still poorly understood, however, is the molecular basis by which certain mutations confer risk for particular pathogens and why many display variable or low penetrance.

Israel et al. explored these questions via a case of severe, recurrent Staphylococcus aureus infections in a young girl of consanguineous birth. Genetic studies identified that she and seven of her immediate unaffected relatives were homozygous for a missense mutation in TIRAP, which encodes an adapter molecule involved in signaling through toll-like receptor (TLR) 2 and TLR4. This mutation impeded subcellular localization of the TIRAP protein and its interaction with TLR2 and the downstream signaling molecule, MyD88. Functionally, this abolished TL2 and TL4 signaling in leukocytes, which was overcome only by prolonged exposure to high concentrations of TLR2 agonists, consistent with known TIRAP-independent TLR signaling in this context.

TLR2 is critical in host defense again S. aureus. Why then was only one family member afflicted by this pathogen while seven relatives with the same mutation were spared? Exposure to the staphylococcal TLR2 agonist, lipoteichoic acid (LTA), but not other generic TLR2 agonists, restored interleukin-6 (IL-6) production in whole blood from all TIRAP-deficient relatives except the affected patient. This suggested that a plasma component could restore signaling in response to Staphlyococcal LTA and confer immune protection. Indeed, anti-LTA antibodies were detected only in the healthy TIRAP-deficient family members, and an anti-LTA monoclonal antibody restored LTA-induced IL-6 production in the initial patient as well as in Tirap–/– mice.

These studies implicate a role for the adaptive immune response, specifically anti-LTA antibodies, in directly rescuing a genetic defect in TLR2 signaling by S. aureus, which otherwise confers significant risk of infection. Although the etiology by which the patient alone failed to generate anti-LTA immunoglobulin G (IgG) is left unanswered, the findings elegantly demonstrate how our adaptive immune response can compensate for genetically determined innate immune defects.